Abstract
Although autoimmunity contributes to rheumatoid arthritis (RA), several lines of evidence challenge the dogma that it is mainly an autoimmune disorder. As RA-associated human leukocyte antigens shape microbiomes and increase the risk of dysbiosis in mucosae, RA might rather be induced by epigenetic changes in long-lived synovial presenting cells, stressed by excessive translocations into joints of bacteria from the poorly cultivable gut, lung, or oral microbiota (in the same way as more pathogenic bacteria can lead to “reactive arthritis”). This narrative review (i) lists evidence supporting this scenario, including the identification of DNA from oral and gut microbiota in the RA synovium (but in also healthy synovia), and the possibility of translocation through blood, from mucosae to joints, of microbiota, either directly from the oral cavity or from the gut, following an increase of gut permeability worsened by migration within the gut of oral bacteria such as Porphyromonas gingivalis; (ii) suggests other methodologies for future works other than cross-sectional studies of periodontal microbiota in cohorts of patients with RA versus controls, namely, longitudinal studies of oral, gut, blood, and synovial microbiota combined with transcriptomic analyses of immune cells in individual patients at risk of RA, and in overt RA, before, during, and following flares of RA.
Highlights
Introduction iationsThe dysbiotic oral microbiota observed in rheumatoid arthritis (RA) is not necessarily causal [1]
Results of IgG1 and IgG2 anti-P. gingivalis antibodies, anticitrullinated peptides antibodies (ACPA), diagnosis for RA, and PD, and a genetic study of the human leukocyte antigen (HLA)-DRB1 region were obtained from 50 patients with
As oral bacteria might contribute to only a subset of cases of RA, those microbiomes should be analyzed together with cofactors that might shift oral, gut, blood, and synovial microbiota by their own, namely, gene polymorphisms, hormonal status stress, habits such as smoking or consumption of highly processed foods, and medication [87]
Summary
Patients with RA were included and data of diagnosis of RA antirheumatic medications, and the presence of periapical abscess were recorded. The repeated translocation of nonreplicative or poorly replicative microorganisms (that might differ according to patients) from mucosal microbiota to various joints/enthesis, favored by mucosal dysbiosis associated with some HLA subtypes [32], and possibly genes of metabolism, would allow for direct interactions of those ectopic pathobionts with immune synovial cells Those contacts, up to the internalization of some bacteria by macrophagic cells, may be sufficient to instigate autoimmunity, first focally and systemically [6], especially following lasting epigenetic changes in long-lived synovial presenting innate cells such as embryologic-derived synovial resident macrophages, and/or stem cells induced by microbial danger signals (“trained immunity”) [39,40,44]. Such translocations might foster lasting dysbiosis in some RA synovia, and subsequent epigenetic changes in presenting cells; (ii) suggest methodologies for future works other than cross-sectional studies of periodontal microbiota in cohorts of patients with RA versus controls
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